Is ATL1 p.Arg217Gln (c.650G>A) pathogenic?

ATL1 p.Arg217Gln (c.650G>A) is classified Pathogenic/Likely pathogenic in ATL1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9978); Very rare (popmax 8.48e-05%, nfe); Associated with ATL1-related disorder.

What condition is associated with ATL1 p.Arg217Gln (c.650G>A)?

ATL1 p.Arg217Gln (c.650G>A) is associated with ATL1-related disorder, hereditary spastic paraplegia 3A (ClinVar).

How common is ATL1 p.Arg217Gln (c.650G>A) in the general population?

ATL1 p.Arg217Gln (c.650G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ATL1 p.Arg217Gln (c.650G>A)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

ATL1 p.Arg217Gln

c.650G>A · rs119476049 · VCV4349

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ATL1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic ✓ concordant with ClinVar
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -13.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 23 kb · p 7.5e-16 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,494 alleles

Overall 6.85e-05% 1/1,460,844 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ATL1
Protein: p.Arg217Gln
Coding: c.650G>A
MANE Select: NM_015915
dbSNP: rs119476049
Type: single nucleotide variant
Location: chr14:50613278 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.36 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 14 PDB
Residue 217: a binding site; a UniProt-annotated variant site (in spg3; loss of gtp-binding; loss of homodimerization; loss of gtpase-dependent fusogenic activity; changed endoplasmic reticulum tubular network membrane organization); the gb1/rhd3-type g domain; a β-strand

Full ATL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ATL1-related disorder

Also linked: hereditary spastic paraplegia 3A

Similar variants

ATL1 p.Arg239Cys Pathogenic/Likely pathogenic ★★ same condition
ATL1 p.Arg239His Likely pathogenic ★★ same condition
ATL1 p.Arg403Pro Likely pathogenic ★★ same condition
ATL1 p.Arg415Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ATL1 p.Arg416Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ATL1 p.Arg495Trp Pathogenic/Likely pathogenic ★★ same condition
ATL1 p.Arg501Ter Pathogenic ★★ same condition
ATL1 p.Gly409Cys Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/atl1-p-arg217gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown